# Dissecting principles of transcription factor binding

> **NIH NIH F32** · STANFORD UNIVERSITY · 2021 · $68,562

## Abstract

Project Summary
Transcription factors (TFs) are the master regulators of cell identity, coordinating precise control of specific
gene networks to drive all the cellular processes necessary for a particular cell fate. The ability of TFs to
regulate cell identity is highlighted by the discovery that ectopic expression of a cocktail of pluripotency TFs
can reprogram somatic cells into induced pluripotent stem cells. Mutations or improper dosage of certain TFs
can also result in various diseases such as cancer. While proper TF regulation is clearly important for normal
cell function, our understanding of how TFs achieve such precise control of over a gene network is lacking.
Specifically, the principles that govern how TFs bind to the correct set of target sites in a cell remain unclear.
For example, TFs generally do not bind all sites containing its target sequence motif within the genome, and
many TF binding sites do not contain the canonical sequence motif. Furthermore, a TF expressed in multiple
cell types can bind to distinct sites in each cell type. This suggests that the cellular context plays a critical role
in determining a TF’s binding sites. To improve our ability to predict and model TF binding and activity, and
therefore drive cell fate, I propose to dissect how the molecular environment within a cell influences where a
TF binds and what the subsequent effects are on chromatin accessibility and gene expression. I hypothesize
that while the binding sequence motif is most important in directing TF binding, the presence of specific
chromatin modifications and cooperative binding partners is important to facilitate TF binding especially at
lower TF expression levels, even for pioneer factors that can access nucleosome-occluded DNA. I will test this
hypothesis through three specific aims. In aim 1, I will examine how TF expression levels affect binding,
chromatin accessibility, and gene expression using new methods I have optimized to measure intracellular
protein levels and chromatin accessibility profiles in the same bulk cell population and in single cells. In aim 2, I
will determine how the presence of specific chromatin modifications can influence where a TF binds in different
cell types. In aim 3, I will directly connect the variability in expression of a TF and its cooperative binding
partners with differential chromatin accessibility profiles observed in the highly heterogeneous common
myeloid progenitor population and determine how this affects cell fate. These studies will provide a detailed
analysis of the role that various factors play in regulating TF binding and enable us to develop more accurate
predictions of where specific TFs are bound in a cell, how they will affect the gene regulatory network to drive a
particular cell state, and how disrupting TF activity can result in disease states. These studies will be carried
out in the Stanford Genetics department, where I will have access to the latest next-generation sequencing
te...

## Key facts

- **NIH application ID:** 10086320
- **Project number:** 5F32GM135996-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Amy Fan Chen
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $68,562
- **Award type:** 5
- **Project period:** 2020-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10086320

## Citation

> US National Institutes of Health, RePORTER application 10086320, Dissecting principles of transcription factor binding (5F32GM135996-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10086320. Licensed CC0.

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